Abstract 254: A Novel Role of Endothelial and Macrophage Epsins in Atherosclerosis

Background: Epsins are a family of ubiquitin-binding endocytic clathrin adaptors. We recently published that endothelial epsins function as critical regulators of tumor angiogenesis by controlling VEGF signaling (JCI, 2012; ATVB, 2013). Our goal is to define the novel role of epsins in endothelial cells (EC) and macrophages in regulating atherogenesis. Methods and Results: We engineered mice with specific deletion of epsins in EC (EC-DKO) or myeloid cells (MΦ-DKO). Strikingly, either EC-DKO or MΦ-DKO mice on ApoE-/- background fed western diet significantly reduced atherosclerotic lesion formation and foam cell accumulation. FACS analysis revealed that epsin deficiency greatly reduced TNFα and LPS-induced adhesion molecule expression (ICAM-1, VCAM-1, P- and E-selectins, CCR2 and MCP-1) in aortic EC and leukocyte recruitment in aorta. Mechanistically, EC epsins promote TNFR/TLR signaling and NF-κB and MAPK activation by recruiting NEMO, an essential NF-κB activator. In macrophages, epsin deficiency did not...